Nicotinic acid (NA; or niacin) is a water-soluble vitamin. In addition to its function as a vitamin, NA, at pharmacological doses, inhibits lipolysis in adipocytes by binding to and activating a G-protein coupled receptor (i.e., NA receptor) in the plasma membrane. The NA receptor (NA-R) is also expressed in a few other tissues, but its functions in non-adipose tissues are unclear. Our preliminary data suggest the novel concepts that there are cells in the brain that express NA-R, and NA stimulates these cells to produce prostaglandins and activate the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this proposal are to test for this potentially novel mechanism for HPA axis activation and to explore its physiological roles. Recently, b-hydroxybutyrate (HB) was shown to be an endogenous ligand for NA-R; plasma HB reaches levels that would substantially stimulate NA-R in various metabolic states, including starvation, diabetes, and anorexia nervosa. Interestingly, all of these metabolic states are characterized by activated HPA axis, but the underlying mechanisms are largely unknown. In light of our finding that NA activates the HPA axis, we hypothesize that the activated HPA axis is due to increased plasma HB that could stimulate NA-R in the brain. Aim 1: Test the hypothesis that NA activates the HPA axis by direct actions in the brain that are mediated through NA-R and prostaglandin synthesis. We will examine in rats whether the HPA axis is activated by intracerebroventricular (icv) infusions of various NA-R agonists, and whether these effects are blocked by an icv infusion of pertussis toxin (PTX; G-protein inhibitor) or cyclooxygenase (COX; or prostaglandin synthase) inhibitors. We will also attempt to identify discrete brain regions involved in the NA effect by examining various brain regions for the expression of NA-R and neuronal activation during NA infusion. Aim 2: Test the hypothesis that plasma HB functions as a key stimulator of the HPA axis via NA- R in the brain and is responsible for HPA axis activation in starvation and diabetes. We will examine in rats whether the HPA axis is activated by an acute elevation of plasma HB level and whether this effect is blocked by an icv infusion of PTX or COX inhibitors. We will also examine the effects of starvation and diabetes on plasma HB, ACTH, and corticosterone levels in wild-type and NA-R knockout mice and test whether the HPA axis is activated in wild-type, but not in NA-R knockout mice despite similar increases in plasma HB levels. Thus, in this project we will test the highly innovated concepts that NA activates the HPA axis via NA-R in the brain and that there is a link between peripheral lipid metabolism (or HB) and neuroendocrine functions (HPA axis). If these concepts are proven true, it would open up many new areas of investigation and provide important clinical implications for activated HPA axis in certain diseases (e.g., diabetes and anorexia nervosa) and unwanted effects of the hypolipidemic drug NA. PUBLIC HEALTH RELEVANCE: The proposed research addresses a novel mechanism for stimulation of cortisol secretion involving the lipid-lowering drug nicotinic acid. The result of the proposed research would provide important clinical implications for excessive cortisol secretion in certain diseases (e.g., diabetes and anorexia nervosa) and unwanted effects of the nicotinic acid therapy for lipid control.